In view of its strategic position at the termini of the two major pathways of glucose production in the liver and kidneys of higher animals, the glucose 6-phosphatase system warrants serious consideration as a potential site to effect clinical management of the hyperglycemia associated with diabetes mellitus. The proposed project is designed to explore the feasibility and potential of intervention at the level of glucose-6-phosphate hydrolysis and to provide a characterization of the components of the glucose 6-phosphatase system in molecular terms. The project involves the following studies: 1) the characterization of the glucose 6-phosphatase systems in liver microsomes of several species to find the best moDel for the human enzyme; 2) a defintive appraisal of the postulated involvement of a glucose-6-phosphate translocase in the function of the enzyme; 3) the purification and characterization of the individual components of the functional glucose 6-phosphatase system; 4) the characterization of the extent and nature of the involvement of insulin, glucagon and epinephrine in the acute regulation of glucose-6-phosphate hydrolysis; and 5) characterization of the catalytic and regulatory properties of glucose 6-phosphatase in situ employing isolated liver parenchymal cells and perfused livers. At the conclusions of these studies, the molecular basis and physiologic significance of the intimate association of the glucose 6-phosphatase system with the membranous components of the liver and kidney endoplasmic reticulum should be defined, and the role of the enzyme in the regulation of blood glucose homeostasis should be established. Hopefully, the findings from this investigation will suggest new and innovative approaches to the clinical management of hepatic and renal glucose production in the diabetic patient.